Although several epidemiological studies pointed out an association between depression and increased risk for cardiovascular (CVD) events, little is known about the mechanisms for this effect. The broad objective of this project is to clarify the role of depression on CVD risk by studying the effects of depression on the cardiovascular system. Using a co-twin study design, 150 monozygotic and dizygotic twin pairs discordant for lifetime diagnosis of major depression drawn from a large national twin registery, the Vietnam Era Twin (VET) Registry will be enrolled. Twin pairs will be compared for 2 indices of altered cardiac function: a) decreased coronary flow reserve, a sensitive indicator of early coronary artery disease, assessed by Positron Emission Tomography (PET) myocardial perfusion imaging; and b) decreased heart rate variability, a risk factor for coronary arrhythmias and sudden death, assessed by means of ambulatory electrocardiographic (Holter) monitoring. Since twins share genetic makeup (which is identical if they are monozygotic) and rearing environment while growing up, they are matched on numerous known and unknown potentially confounding factors. Another aim of this project is to determine the relative contributions of genetic and environmental factors (such as life stressors) in the association between depression and abnormal cardiac function, by comparing the size of the intra-pair difference in cardiac parameters between depression-discordant twins. Twin pairs who are free of CVD and discordant for lifetime depression in previous surveys of the VET registry, will be invited to participate. Participants will travel to our institution in order to undergo confirmation of depression diagnosis by means of the Structured Clinical Interview for DSM-IV (SCID), PET myocardial imaging, and 24-hour Holter monitoring. Blood will also be drawn in order to investigate the role of biological mediators such as increase in hypothalamic-pituitary-adrenocortical and sympathomedullary activity. Besides extending our knowledge of the mechanisms linking depression to CVD risk, the findings of this project will help in the design of more effective approaches to the primary prevention of CVD.